|Publication number||US6210326 B1|
|Application number||US 08/888,734|
|Publication date||Apr 3, 2001|
|Filing date||Jul 7, 1997|
|Priority date||Jan 6, 1995|
|Also published as||DE19501159A1, DE19501159B4|
|Publication number||08888734, 888734, US 6210326 B1, US 6210326B1, US-B1-6210326, US6210326 B1, US6210326B1|
|Original Assignee||Rudolf Ehwald|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (5), Referenced by (81), Classifications (15), Legal Events (5)|
|External Links: USPTO, USPTO Assignment, Espacenet|
1. Field of the Invention
The present invention relates to a microsensor for determination of glucose and other analytes in liquids based on affinity viscosimetry.
2. Description of the Related Art
Affinity sensors are important for analytics, as there exists a large number of affinity receptors, e.g. antibodies, which are not catalytically active. The technical task to transduce concentration dependent binding of analytes to the suitable receptor into an electrical signal within a microsensor, is an actual one, which is not easy to solve. A promising way for solving this task consists in the inclusion of receptor proteins and polymer affinity ligands in the lumen of a dialysis hollow fiber with a membrane which is permeable to the analyte (schultz, J. S. and Sims, G., 1979: Affinity sensors for individual metabolites, Biotechn. Bioeng. Symp-9, 65-71, Schultz, J. S., 1982, Optical sensor of plasma constituents, U.S. Pat. 4,344,438). The analyte-dependent dissociation of the receptor from the polymer ligand may be made detectable by diffusion of the polymer binding partner between the immobilized binding site and the ligand phase within the fiber lumen (Schultz, J. S., Mansouni, S. and Goldstein, I. J., 1982: Affinity sensor, A new technique for developing implantable sensor for glucose and other metabolites, Diabetes Care, 5,245-253, Knoll, D., Ehwald, K. E., Ehwald, R. Sorge, E., Ballersätdt, R. und Bolleroth, M., 1991: A silicon based microsystem for continuous in vivo glucose monitoring using a new reversible measuring principle) or by Fluorescence quenching (Meadows, D. L. and Schultz J. S., 1988, Fiberoptic bionsensor based on fluorescence energy transfer, Talante 35, 145-150). An interesting and simple alternative to the mentioned techniques is an affinity viscosimetry, measuring the concentration of affinity bonds mechanically in a direct manner. Affinity viscosimetry with dispersions of dextran and Concanavalin A is suitable for glucose determination in the blood sugar range and may be carried out with dialysis hollow fibers. The until now described hollow fiber viscosimeters do not have an electrical signal transducer and are unstable because of nonavoidable volume changes of the sensitive polymer phase (Ballerstädt, R. und Ehwald, R., 1992, Affinitätssensor, DE-P4203466, Ballerstädt, R., und Ehwald, R, 1994: Suitability of aqueous dispersion of dextran and Concanavalin A for glucose sensing in different variants of the affinity sensor, Biosensors and Bioelectronics, 9, 557-567).
An important field of application of microsensors is the on-line registration of analytes in body fluids, e.g. of glucose in the blood. Affinity viscosimetry is generally suitable for measuring relevant analytes which are known to bind to affinity receptor proteins. A miniaturized implantable affinity viscosimeter combined with a dialysis chamber or hollow fiber would therefore have promising applications. Such viscosimeter is not known.
It is an object of the present invention to produce a reliably working sensor on the base of affinity viscosimetry which can be sufficiently miniaturized by microsystem technology for implantation purposes.
This and other objects of the present invention are attained by a hydraulic coupling of the sensitive polymer system dissolved in water and a measuring signal delivering system to a closed completely liquid-filled conducting system (hollow conductor). The analyte-sensitive polymer solution and eventually one or more other liquids which are not miscible with this polymer solution are mobile on a closed path. The measuring system contains a micromotor for driving the movement of the analyte-sensitive polymer solution and a pressure-, volume- or flow-sensitive unit delivering signals which are unequivocally related to the viscosity of the liquids.
For example, a hollow conductor with solid walls may be tightly connected at both ends with the endings of a hollow fiber which is filled with the sensitive polymer solution. The whole hollow conductor is filled with a liquid which can transduce forces between a pumping micromotor and the sensitive polymer solution within the fiber. Possible micromotors are magnetic particles or liquids in the magnetic field, dielectrically moved solids or liquids. The liquid movement within the hollow conductor is registrated either optically by photosensors at dragged interfaces or solids, or electromechanically by the reaction of the frictional reactive force on the micromotor. The micromotor is a microsystem on the base of silicon technology, for its application in vivo a microelectronic system with integrated transducing elements for energy and signals is opportune.
According to the invention, there exist several variants, enabling or facilitating galvanic uncoupling of the extracorporal monitoring and energy supply form intracorporal viscosimetric sensing device. For efficient transduction of energy and information it is especially lucrative that apart from the dialysis fiber or chamber, the hollow conductor is filled by a liquid which is nonmiscible with water. This enables the application of dielectric micromotors which can realize oscillating liquid movements with high efficiency and can deliver well transferable electrical signals (capacity based) for streaming. The application of the nonhydrophilic liquid in the hollow conductor enables the construction of the sensor according to the invention in a simple way and allows for fast diffusional equilibration of the analyte between the whole sensitive polymer phase and the external medium. The surface forces resulting from the contact of the different liquids may be used for prevention of rotating movements of the liquid through the hollow conductor and for restriction of the oscillating movements within a certain amplitude.
Further advantages of the invented principle are the complete independence from the external pressure, as changes in external pressure cannot induce liquid movements in a closed system completely filled with noncompressible liquid, and the potentially small volume of the device, as the sensitive part (dialysis chamber or hollow fiber) has a very small volume.
FIG. 1 is a diagrammatic view of a microsensor of a first embodiment of the present invention;
FIG. 2 is a diagrammatic view of a microsensor of a second embodiment of the invention;
FIG. 3 is a sectional view along line III—III of FIG. 2; and
FIG. 4 is a sectional view on line IV—IV of FIG. 2.
FIG. 1 shows a sensor configuration of the first embodiment and FIGS. 2-4 show a sensor of the second embodiment of the present invention.
A dialysis chamber is shown in FIG. 1.
The dialysis chamber consisting of a hollow fiber (1 b) filled with a sensitive polymer solution (1 a) is connected with an electrostatic micromotor into a hydraulically closed functional unit. The micromotor consists of a metallic (active) membrane (2 b), having a first side and a second side a perforated leading membrane support (2 a) which is not insulated from the membrane, an insulating ring (2 c) which also defines the distance of the membrane to the metallic tap electrodes (2 d) and the perforated heading top body (2 e). The ends of the hollow fiber (1 b) are stuck in the perforations of the membrane support (2 a) and of the top body (2 e). The inner volume of the micromotor and a part of the bordering hollow fiber are filled with pure silicon oil (1 c), which forms stable interfaces (1 d) to the analyte-sensitive polymer solution in the hollow fiber and is not miscible with this solution. The first side of the active membrane limits a variable first hollow space (1 c) which is connected with one end of the dialysis hollow fiber containing said analyte-sensitive polymer solution. The second side of the active membrane limits a second variable hollow space (1 c) which is connected with the other end of the dialysis hollow fiber. The hollow spaces at both sides of the active membrane being separated from the surrounding of the hollow conductor by rigid vacuum tight walls.
The membrane can be moved towards the top electrode by the high electric field in the silicon oil, if a DC or AC voltage is applied between the membrane support (2 a) and the top body (2 e). The liquid motion in the hollow fiber can be controlled measuring the capacitance between these electrodes as a function of time.
To realize the measuring process in vivo, the membrane support (2 a) and the top body (2 e) are both connected to a miniaturized transducer unit (4) using a coaxial cable (3). The transducer unit can be wirelessly coupled by means of the coils (5 a) and (5 b) with the microprocessor-controlled monitoring unit (6) which contains also a power supply. The parts (1)-(4) of the described microsystem, including the first transducer coil (5 a), may be completely implanted in the body of the diabetic patient, the hollow fiber being inserted for example into a vein or embedded in the subcutane tissue fluid. The extracorporal part of the microsystem (6) is permanently or temporarily placed on the skin of the patient near to the implanted coil (5 a). The implanted part of the microsystem is activated by the energy delivered from the external monitoring unit and does not need an own power supply.
The glucose measurement can be carried out continuously or in adequate time intervals. The described microsystem can also be used to monitor the glucose concentration in a plant organism, a bioreactor or waste water.
In the embodiment of FIGS. 2-4 the micromotor is also used as a sensor for the liquid motion. The micromotor is composed of two thermically bonded Si-chips and. In the top chip (2 e) a flat U-shaped deepening is etched forming a flat microchannel between the openings (2 i) after the bonding process with the bottom chip (2 a). In the bottom chip (2 a) two implanted electrodes (2 d) are placed symmetrically at the bottom of the U-shaped microchannel, pn-insulated from the substrate and from each other. These electrodes are connected via the bond pads (2 g) with a miniaturized capacity measurement set up (4). The capacity of each electrode is measured with respect to the contract (2 h) on the chip (2 e) consisting of highly dosed silicon. The silicon dioxide layers (2 k) with a thickness of about 1 μm insulate the top chips from the bottom whereas the inside walls at the microchannel are covered by a considerable thinner insulator (thickness about 0.05 μm). The channel is filled with the liquid (1 c), which includes a very small volume of another liquid (1 f). The small liquid volume (1 f) has a high dielectric constant and/or electric conductance (e.g. water) and is not miscible with the liquid (1 c) which is a nonconducting silicon oil with a low dielectric constant, thus forming a stable interface with this liquid. Stable interfaces are also formed between the silicon oil (1 c) and the analyte-sensitive polymer solution (1 a) in the hollow fiber (1 b), connected to the microchannel with the openings (2 i). The U-shaped microchannel, and the hollow fiber are completely filled with the liquids (1 d), (1), and (1 a) without any compressible gas includings. If an HF-voltage source is connected with one of the electrodes (2 f), the liquid (1 f) will be drawn completely to the corresponding channel region, this way increasing the capacitance between this electrode and the top chip (2 e) nearly by the factor (h/dox)×(εox/εoil). h=height of the microchannel, dox=thickness of the oxid covering the microchannel, εox, εoil=dielectic constants of oxide and silicon oil.
The pressure driving the liquid (1 f) towards the HF-biased electrode can be estimated by calculating the increase of the medium electrical energy stored in the condensator at the applied HV-voltage, if the border area is displaced by a little increment. In our example, the pressure is about 60 mbar at an effective voltage of 30 V. This pressure is sufficient to displace the sensitive liquid (1 a) with a velocity linearly dependent on the viscosity of said liquid. If the other electrode is connected with the HF voltage source, the liquids move back and the measuring cycle can start again. For both directions the viscosity can be obtained directly from the capacity change at one of the electrodes.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US4832034 *||Apr 9, 1987||May 23, 1989||Pizziconi Vincent B||Method and apparatus for withdrawing, collecting and biosensing chemical constituents from complex fluids|
|US5156972 *||Sep 5, 1990||Oct 20, 1992||The State Of Israel, Atomic Energy Commission, Soreq Nuclear Research Center||Analyte specific chemical sensor with a ligand and an analogue bound on the sensing surface|
|US5174291 *||May 15, 1990||Dec 29, 1992||Rijksuniversiteit Te Groningen||Process for using a measuring cell assembly for glucose determination|
|US5269891 *||Jan 26, 1993||Dec 14, 1993||Novo Nordisk A/S||Method and apparatus for determination of a constituent in a fluid|
|US5615671 *||Jul 11, 1996||Apr 1, 1997||Siemens-Elema Ab||Processes and devices for continuously monitoring levels of analyte|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US6366794 *||Nov 19, 1999||Apr 2, 2002||The University Of Connecticut||Generic integrated implantable potentiostat telemetry unit for electrochemical sensors|
|US6844960 *||Sep 24, 2002||Jan 18, 2005||Eastman Kodak Company||Microelectromechanical device with continuously variable displacement|
|US6877360 *||Feb 20, 2003||Apr 12, 2005||Rockwell Automation Technologies, Inc.||System and method for dynamic lubrication adjustment for a lubrication analysis system|
|US6938463||Aug 30, 2002||Sep 6, 2005||Disetronic Licensing Ag||Method for affinity viscosimetry and viscosimetric sensor|
|US7134323||Jan 24, 2005||Nov 14, 2006||Rockwell Automation Technologies, Inc.||System and method for dynamic lubrication adjustment for a lubrication analysis system|
|US7166458||Dec 12, 2003||Jan 23, 2007||Bio Tex, Inc.||Assay and method for analyte sensing by detecting efficiency of radiation conversion|
|US7226414||Oct 3, 2003||Jun 5, 2007||Biotex, Inc.||Method and apparatus for analyte sensing|
|US7236812||Aug 27, 2004||Jun 26, 2007||Biotex, Inc.||System, device and method for determining the concentration of an analyte|
|US7284413 *||May 28, 2001||Oct 23, 2007||Rudolf Ehwald||Method and apparatus for measuring viscosity|
|US7493799||Jul 11, 2006||Feb 24, 2009||Rockwell Automation Technologies, Inc.||System and method for dynamic lubrication adjustment for a lubrication analysis system|
|US7514038||Jun 4, 2004||Apr 7, 2009||Medtronic Minimed, Inc.||Sensor substrate and method of fabricating same|
|US7690246||Jan 12, 2009||Apr 6, 2010||Rockwell Automation Technologies, Inc.||System and method for dynamic lubrication adjustment for a lubrication analysis system|
|US7736309||Dec 31, 2002||Jun 15, 2010||Medtronic Minimed, Inc.||Implantable sensor method and system|
|US7789829||Oct 22, 2003||Sep 7, 2010||Ecole Polytechnique Federale De Lausanne||Sensor system for determining the concentration of glucose in blood|
|US8292808||Oct 23, 2012||Medtronic Minimed, Inc.||Implantable sensor method and system|
|US8364217||Jun 8, 2007||Jan 29, 2013||Biotex, Inc.||System, device and method for determining the concentration of an analyte|
|US8404495||Mar 26, 2013||Biotex, Inc.||Device and method for analyte sensing|
|US8465466||Nov 22, 2004||Jun 18, 2013||Medtronic Minimed, Inc||Method and system for non-vascular sensor implantation|
|US8500637||Jul 14, 2009||Aug 6, 2013||Ecole Polytechnique Federale De Lausanne (Epfl)||Viscosimetric biosensor for monitoring analyte levels|
|US8506550||Nov 24, 2005||Aug 13, 2013||Medtronic Minimed, Inc.||Method and system for non-vascular sensor implantation|
|US8574164||Sep 28, 2012||Nov 5, 2013||Nyxoah SA||Apparatus and method for detecting a sleep disordered breathing precursor|
|US8577464||Sep 28, 2012||Nov 5, 2013||Nyxoah SA||Apparatus and methods for feedback-based nerve modulation|
|US8577465||Sep 28, 2012||Nov 5, 2013||Nyxoah SA||Modulator apparatus configured for implantation|
|US8577466||Sep 28, 2012||Nov 5, 2013||Nyxoah SA||System and method for nerve modulation using noncontacting electrodes|
|US8577467||Sep 28, 2012||Nov 5, 2013||Nyxoah SA||Apparatus and method for controlling energy delivery as a function of degree of coupling|
|US8577468||Sep 28, 2012||Nov 5, 2013||Nyxoah SA||Apparatus and method for extending implant life using a dual power scheme|
|US8577472||Sep 28, 2012||Nov 5, 2013||Nyxoah SA||Systems and methods for determining a sleep disorder based on positioning of the tongue|
|US8577478||Sep 28, 2012||Nov 5, 2013||Nyxoah SA||Antenna providing variable communication with an implant|
|US8588941||Sep 28, 2012||Nov 19, 2013||Nyxoah SA||Device and method for modulating nerves using parallel electric fields|
|US8644957||Sep 28, 2012||Feb 4, 2014||Nyxoah SA||Electrode configuration for implantable modulator|
|US8700183||Sep 28, 2012||Apr 15, 2014||Nyxoah SA||Devices and methods for low current neural modulation|
|US8718776||Sep 28, 2012||May 6, 2014||Nyxoah SA||Apparatus and method to control an implant|
|US8798773||Dec 30, 2013||Aug 5, 2014||Man & Science, SA||Electrode configuration for implantable modulator|
|US8821793||Oct 25, 2007||Sep 2, 2014||Medtronic Minimed, Inc.||Sensor substrate and method of fabricating same|
|US8929999||May 28, 2014||Jan 6, 2015||Adi Maschiach||Electrode configuration for implantable modulator|
|US8979885||Feb 24, 2012||Mar 17, 2015||Elwha Llc||Devices, systems, and methods to control stomach volume|
|US8979887||Feb 24, 2012||Mar 17, 2015||Elwha Llc||Devices, systems, and methods to control stomach volume|
|US8986337||Feb 24, 2012||Mar 24, 2015||Elwha Llc||Devices, systems, and methods to control stomach volume|
|US8989868||Sep 30, 2013||Mar 24, 2015||Hyllio SA||Apparatus and method for controlling energy delivery as a function of degree of coupling|
|US9044612||Sep 30, 2013||Jun 2, 2015||Adi Mashiach||Apparatus and method for extending implant life using a dual power scheme|
|US9061151||Mar 24, 2014||Jun 23, 2015||Adi Mashiach||Apparatus and method to control an implant|
|US9248290||Aug 4, 2014||Feb 2, 2016||Adi Mashiach||Apparatus and methods for feedback-based nerve modulation|
|US9248291||Oct 23, 2014||Feb 2, 2016||Adi Mashiach||Hypertension therapy implant apparatus|
|US9302093||Sep 28, 2012||Apr 5, 2016||Nyxoah SA||Devices and methods for delivering energy as a function of condition severity|
|US9314613||Sep 28, 2012||Apr 19, 2016||Adi Mashiach||Apparatus and methods for modulating nerves using parallel electric fields|
|US9317662||May 4, 2012||Apr 19, 2016||Elwha Llc||Devices, systems, and methods for automated data collection|
|US9358392||Jan 5, 2015||Jun 7, 2016||Adi Mashiach||Electrode configuration for implantable modulator|
|US9364174||Jan 21, 2014||Jun 14, 2016||The Trustees Of Columbia University In The City Of New York||MEMS affinity sensor for continuous monitoring of analytes|
|US9375145||Dec 19, 2012||Jun 28, 2016||Elwha Llc||Systems and methods for controlling acquisition of sensor information|
|US9400233||Sep 27, 2011||Jul 26, 2016||The Trustees Of Columbia University In The City Of New York||Sensors for long-term and continuous monitoring of biochemicals|
|US9403009||Sep 28, 2012||Aug 2, 2016||Nyxoah SA||Apparatus and methods for implant coupling indication|
|US9409013||Sep 30, 2013||Aug 9, 2016||Nyxoah SA||Method for controlling energy delivery as a function of degree of coupling|
|US9415215||Oct 16, 2015||Aug 16, 2016||Nyxoah SA||Methods for treatment of sleep apnea|
|US9415216||Oct 16, 2015||Aug 16, 2016||Nyxoah SA||Devices for treatment of sleep apnea|
|US9421372||Oct 23, 2014||Aug 23, 2016||Adi Mashiach||Head pain management device having an antenna|
|US20030143746 *||Jan 31, 2002||Jul 31, 2003||Sage Burton H.||Self-calibrating body anayte monitoring system|
|US20040058469 *||Sep 24, 2002||Mar 25, 2004||Eastman Kodak Company||Microelectromechanical device with continuously variable displacement|
|US20040064133 *||Dec 31, 2002||Apr 1, 2004||Medtronic-Minimed||Implantable sensor method and system|
|US20040132169 *||Dec 12, 2003||Jul 8, 2004||Ralph Ballerstadt||Device and method for analyte sensing|
|US20040221643 *||Apr 19, 2004||Nov 11, 2004||Rudolf Ehwald||Method for affinity viscosimetry and viscosimetric sensor|
|US20040223875 *||Jun 4, 2004||Nov 11, 2004||Medtronic Minimed, Inc.||Sensor substrate and method of fabricating same|
|US20050033133 *||Aug 3, 2004||Feb 10, 2005||Clifford Kraft||Implantable chip medical diagnostic device for bodily fluids|
|US20050090866 *||Nov 22, 2004||Apr 28, 2005||Medtronic Minimed, Inc.||Method and system for non-vascular sensor implantation|
|US20060079858 *||Nov 24, 2005||Apr 13, 2006||Medtronic Minimed, Inc.||Method and system for non-vascular sensor implantation|
|US20060100493 *||Oct 22, 2003||May 11, 2006||Sigfrid Strassler||Sensor system for determining the concentration of glucose in blood|
|US20070117223 *||Jan 22, 2007||May 24, 2007||Ralph Ballerstadt||Device and method for analyte sensing|
|US20070249917 *||Jun 8, 2007||Oct 25, 2007||Ralph Ballerstadt||System, device and method for determining the concentration of an analyte|
|US20080050281 *||Oct 25, 2007||Feb 28, 2008||Medtronic Minimed, Inc.||Sensor substrate and method of fabricating same|
|US20090030297 *||Sep 16, 2008||Jan 29, 2009||Medtronic Minimed, Inc.||Implantable sensor method and system|
|US20090259112 *||Apr 9, 2008||Oct 15, 2009||Searete Llc, A Limited Liability Corporation Of The State Of Delaware||Sensors|
|US20090259215 *||Apr 9, 2008||Oct 15, 2009||Searete Llc, A Limited Liability Corporation Of The State Of Delaware||Methods and systems associated with delivery of one or more agents to an individual|
|US20090259217 *||Jun 5, 2008||Oct 15, 2009||Searete Llc, A Limited Liability Corporation Of The State Of Delaware||Methods and systems associated with delivery of one or more agents to an individual|
|US20100022854 *||Jan 28, 2010||Clifford Kraft||Implantable Chip Medical Diagnostic Device for Bodily Fluids|
|US20100241063 *||Oct 22, 2008||Sep 23, 2010||Sensile Pat Ag||Liquid Flow Sensing System|
|US20110124985 *||Jul 14, 2009||May 26, 2011||Ecole Polytechnique Federale De Lausanne (Epfl)||Viscosimetric biosensor for monitoring analyte levels|
|US20140000344 *||Jun 19, 2013||Jan 2, 2014||Ihp Gmbh||MEMS-Microviscometer|
|DE102008002050A1||May 28, 2008||Dec 10, 2009||Bst Bio Sensor Technologie Gmbh||Mikrodialysekammersystem mit eingeschlossenen kolloidalen Stoffen und Verfahren zu dessen Herstellung|
|EP1415590A1 *||Oct 28, 2002||May 6, 2004||Ecole Polytechnique Federale De Lausanne||Glucose sensor|
|EP1438029A2 *||Oct 23, 2002||Jul 21, 2004||Medtronic MiniMed, Inc.||Method and system for non-vascular sensor implantation|
|WO2004037079A1 *||Oct 22, 2003||May 6, 2004||Ecole Polytechnique Federale De Lausanne||Sensor system for determining the concentration of glucose in blood|
|WO2008102001A1 *||Feb 21, 2008||Aug 28, 2008||Humboldt-Universität Zu Berlin||Method for measuring viscosity, and viscosimetric affinity sensor|
|U.S. Classification||600/365, 128/903, 600/345, 600/347, D24/186|
|International Classification||B01L3/00, C12Q1/00, A61B5/00|
|Cooperative Classification||Y10S128/903, C12Q1/006, A61B5/14532, B01L3/5027, A61B2562/028|
|European Classification||A61B5/145G, C12Q1/00B6B|
|Oct 4, 2004||FPAY||Fee payment|
Year of fee payment: 4
|Oct 3, 2008||FPAY||Fee payment|
Year of fee payment: 8
|Nov 12, 2012||REMI||Maintenance fee reminder mailed|
|Apr 3, 2013||LAPS||Lapse for failure to pay maintenance fees|
|May 21, 2013||FP||Expired due to failure to pay maintenance fee|
Effective date: 20130403